The applicant, James M Dominguez II, will be entering his fifth year of doctoral training in the discipline of exercise physiology under the supervision of Michael D. Delp at the University of Florida. Mr. Dominguez is the senior doctoral student in the laboratory and has completed all components requisite for graduation short of the proposed dissertation studies. Mr. Dominguez has trained extensively with the proposed microvessel cannulation technique, having earned authorship on at least nine individual manuscripts at various stages of completion. The following proposed dissertation studies are expected to lead to a minimum of three publications (two first-author) for Mr. Dominguez. This will contribute significantly to his immediate goal of obtaining a post-doctoral fellowship at a major research institution, where he plans to investigate mechanisms of bone cell mechanotransduction and functional genomics. Subsequent to his post-doctoral fellowship(s), he plans to obtain a faculty research tenure-track position at a major research institution. Bone loss disorders are associated with impaired blood flow and/or vascular defects [3, 5-10]. The work that directly preceded Mr. Dominguez'proposed dissertation studies was that of Prisby et al. 2007 [4], which included Mr. Dominguez as an author. The primary finding from that work was that old age-associated bone loss in rats was associated with decreased bone blood flow and decreased endothelium-dependent nitric oxide (NO) bioavailability in the bone vasculature. Mr. Dominguez'proposed dissertation work will investigate functional properties of the bone vasculature after interventions that result in net bone gain. The overall hypothesis of the proposal is that endurance exercise training and statin treatment will restore/increase endothelial function in the bone vasculature and increase structural properties at the corresponding bone (femur). Affirmation of these hypotheses would continue to support several mechanisms by which the vasculature may directly influence bone structure (Figure 1). Results from these two studies will be particularly valuable, as they have the capacity to support or refute the contention that vascular mechanisms control bone cell activity [11-13] independent of mechanical loading. If our hypotheses are upheld, improving vascular endothelial cell function may represent a novel strategy to increase parameters of bone health. To date, Mr. Dominguez has completed approximately 30% percent of the work proposed herein. The studies that remain to be completed will take place in two separate facilities that are fully outfitted with requisite equipment and experienced personnel. PUBLIC HEALTH RELEVANCE: Ten million individuals in the United States suffer from osteoporosis which contributes to at least 1.5 million fractures annually and an estimated $17-billion in spending [14]. Pharmacologic interventions (e.g. bisphosphonates) do successfully attenuate age-related bone loss, but may subsequently predispose the bone to increased microdamage burden [15]. Determination of anabolic pathways that contribute to bone accretion could provide a much needed solution for bone loss during conditions where vigorous physical activity is contraindicated or limited, such as space flight, frail elderly, cancer treatment and spinal injury.